The present invention relates to a novel class of compounds, their salts, pharmaceutical compositions comprising them and their use in therapy of the human body. In particular, the invention relates to novel diaryl ether derivatives which inhibit the processing of APP by γ-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease. The compounds of the invention also spare the Notch signaling pathway. As such, the compounds of the invention are believed to halt or potentially reverse the progression of Alzheimer's disease without the development of toxicities mediated by Notch inhibition.
Alzheimer's disease (AD) is the most prevalent form of dementia. Although primarily a disease of the elderly, affecting up to 10% of the population over the age of 65, AD also affects significant numbers of younger patients with a genetic predisposition. It is a neurodegenerative disorder, clinically characterized by a progressive loss of memory and cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers. These plaques are mainly comprised of fibrillar aggregates of β-amyloid peptide (Aβ) (Glenner G G and Wong C W (1984) Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysical research Communications, 120(3); 885-890). The role of secretases, including that of γ-secretase, in the processing of amyloid precursor protein (APP) to form Aβ is well documented in the literature. Aβ is generated by proteolytic processing of APP by two enzymes, β-amyloid cleavage enzyme (BACE) and γ-secretase (FIG. 1; Selkoe D J (2001) Alzheimer's disease: genes, proteins, and therapy. Physiological Review. 81(2):741-766). γ-Secretase is a complex comprised of four proteins: presenilin (presenilin-1 or -2), nicastrin, APH-1 and PEN-2 (Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T (2003) The role of presenilin cofactors in the gamma-secretase complex. Nature. 422(6930):438-441; Kimberly W T, LaVoie M J, Ostaszewski B L, Ye W, Wolfe M S, Selkoe D J (2003) Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proceedings of the National Academy of Sciences. 100(11):6382-6387; Edbauer D, Winkler E, Regula J T, Pesold B, Steiner H, Haass C (2003) Reconstitution of gamma-secretase activity. Nature Cell Biology. 5(5):486-488.). Presenilin-1 and -2 contain transmembrane aspartyl residues that have been shown to be essential for the catalytic activity of the complex (Wolfe M S, Xia W, Ostaszewski B L, Diehl T S, Kimberly W T, Selkoe D J (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999 398(6727):513-517). The majority of the mutations linked to the early onset, familial form of AD (FAD) are associated with either PS-1 or PS-2 (Schemer D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird T D, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Medicine. 2(8):864-870; Duff K, Eckman C, Zehr C, Yu X, Prada C M, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon M N, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 383(6602):710-713; Lernere C A, Lopera F, Kosik K S, Lendon C L, Ossa J, Saida T C, Yamaguchi H, Ruiz A, Martinez A, Madrigal L, Hincapie L, Arango J C, Anthony D C, Koo E H, Goate A M, Selkoe D J, Arango J C (1996) The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nature Medicine. 2(10):1146-1150; Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Molter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens Jr, Kim 5, Schenk D, Fraser P, St George Hyslop P, Selkoe D J (1997) Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nature Medicine. 3(1):67-72). γ-Secretase processes a number of other type I membrane proteins that have undergone a prerequisite ectodomain shedding (Lleó A (2008) Activity of gamma-secretase on substrates other than APP. Current Topics in Medicinal Chemistry. 8(1):9-16).
In addition to processing APP, γ-secretase cleaves the Notch family of receptors. Genetic evidence indicates that γ-secretase activity is critically required for Notch signaling and functions (Shen J, Bronson R T, Chen D F, Xia W, Selkoe D J, Tonegawa S (1997) Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 89(4):629-639; Wong P C, Zheng H, Chen H, Becher M W, Sirinathsinghji D J, Trumbauer M E, Chen H Y, Price D L, Van der Ploeg L H, Sisodia S S (1997) Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 387(6630):288-292). Notch is an evolutionarily conserved and widely expressed single-span type I transmembrane receptor that plays a prominent role in regulating cell fate decisions in the developing embryo (Artavanis-Tsakonas S, Rand M D, Lake R J (1999) Notch signaling: cell fate control and signal integration in development. Science. 284(5415):770-776). The role of Notch in the adult remains unclear but Notch proteins are expressed in various adult tissues and are thought to play a role in regulating stem cell differentiation. Four Notch genes have been identified in mammals (Notch 1-4); all four Notch proteins are cleaved by γ-secretase (Saxena M T, Schroeter E H, Mumm J S, Kopan R (2001) Murine notch homologs (N-1-4) undergo presenilin-dependent proteolysis. Journal of Biological Chemistry. 276(43):40268-40273). Notch activation is induced by binding, in trans, to the Delta/Serrate/LAG2 family of transmembrane ligands. Notch signal transduction is mediated by three cleavage events: (a) cleavage at Site 1 in extracellular domain; (b) cleavage at Site 2 just N-terminal to the extracellular/transmembrane domain boundary following ligand binding; and (c) cleavage at Site 3 (S3) within the transmembrane near the transmembrane/cytoplasmic domain boundary. Site 3 cleavage is required for release of Notch intracellular domain (NICD) and is mediated by γ-secretase (Schroeter E H, Kisslinger J A, Kopan R (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 393(6683):382-386). NICD activates transcription mediated by the (CSL) CBF1/Serrate/LAG-1 family of DNA binding proteins and induces expression of various genes. NICD-regulated transcription is thought to be a key component of Notch-mediated signal transduction.
The development of γ-secretase inhibitors to block APP cleavage and Aβ generation is hampered by the potential for mechanism-based toxicity due to inhibition of Notch processing. Notch-related toxicities have been observed in studies where animals have been dosed subchronically with γ-secretase inhibitors. Intestinal goblet cell metaplasia is consistently observed following three or more days of treatment (Searfoss G H, Jordan W H, Calligaro D O, Galbreath E J, Schirtzinger L M, Berridge B R, Gao H, Higgins M A, May P C, Ryan T P (2003) Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional gamma-secretase inhibitor. Journal of Biological Chemistry. 278(46):46107-46116; Wong G T, Manfra D, Poulet F M, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine J S, Lee H J, Zhang L, Higgins G A, Parker E M (2004) Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. Journal of Biological Chemistry. 279(13):12876-12882; Milano 3, McKay 3, Dagenais C, Foster-Brown L, Pognan F, Gadient R, Jacobs R T, Zacco A, Greenberg B, Ciaccio P J (2004) Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicological Sciences. 82(1):341-358; van Es J H, van Gijn M E, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton D J, Radtke F, Clevers H (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 435(7044):959-963). In addition, Notch function appears to be critical for the proper differentiation of T and B lymphocytes (Hadland B K, Manley N R, Su D, Longmore G D, Moore C L, Wolfe M S, Schroeter E H, Kopan R (2001) Gamma-secretase inhibitors repress thymocyte development. Proceedings of the National Academy of Sciences. 98(13):7487-7491; Doerfler P, Sheannan M S, Perlmutter R M (2001) Presenilin-dependent gamma-secretase activity modulates thymocyte development. Proceedings of the National Academy of Sciences. 98(16):9312-9317). Thus, pharmacologically targeting γ-secretase activity requires agents that selectively block Aβ while minimally inhibiting activity towards Notch.
The present invention provides a novel class of diaryl ether derivatives which inhibit the processing of APP by the putative γ-secretase while sparing Notch signaling pathway, and thus are useful in the treatment or prevention of AD. WO 2004/089911A1 discloses a class of pyrazole derivatives as gamma-secretase inhibitors. However, compounds disclosed in WO 2004/089911 A1 exhibit poor metabolic stability, which translates into poor in vivo pharmacokinetics and little or no efficacy in vivo. Compounds of the present invention possess favorable in vivo pharmacokinetics and are efficacious (inhibit the processing of APP) in vivo.